Alphaviruses can cause massive outbreaks of human disease ranging from arthritis and encephalitis to haemorrhagic fever. Therefore, understanding the mechanism(s) of pathogenesis and the virus-host interaction(s) is crucial in developing therapeutics against these viruses. Studies have demonstrated that the type I interferon (IFN) system play an important role in determining the outcome of alphavirus infections. However, little is known about these initial interactions. Evidence from our lab suggests that the Sindbis Virus (AR86) nonstructural proteins may antagonize type I IFN induction independently of the nonstructural proteins role in viral RNA synthesis, thus providing the virus an effective mechanism to evade the host's type I IFN response and establish productive infection. Therefore, the goals of this project are to characterize the virus IFN antagonism by 1) defining the mechanism of AR86 nonstructural protein antagonism, 2) mapping the protein domains that are required for efficient IFN inhibition, and 3) identifying if this is a common trait of all alphaviruses. These studies will further our overall understanding of alphavirus pathogenesis and viral pathogenesis in general, with the ultimate goal of improving efforts to fight the infection. Alphaviruses represent re-emerging pathogens with the ability to affect both public health and economy. The type I interferon system is one of the first innate defense mechanisms against viral infections, and interactions with alphaviruses have a major impact on the outcome of the viral infections. Therefore, the proposed studies evaluating the role of the alphavirus nonstructural proteins in regulating the type I IFN system will significantly advance our understanding of alphavirus biology and pathogenesis, thus leading to improved therapeutics. [unreadable] [unreadable] [unreadable]